U.S. patent number 5,352,679 [Application Number 08/083,453] was granted by the patent office on 1994-10-04 for use of rifaximin and pharmaceutical formulations containing it in the treatment of gastric dyspepsia caused by helicobacter pylori.
This patent grant is currently assigned to Alfa Wassermann S.p.A.. Invention is credited to Antonella Ferrieri, Leone G. Rotini.
United States Patent |
5,352,679 |
Ferrieri , et al. |
October 4, 1994 |
Use of rifaximin and pharmaceutical formulations containing it in
the treatment of gastric dyspepsia caused by helicobacter
pylori
Abstract
The antibiotic known by the name rifaximin (INN) is active
orally in the treatment of gastric dyspepsia caused by bacteria
known as Helicobacter pylori. Rifaximin may be administered in any
oral pharmaceutical form, particularly tablets, capsules, sugar
coated tablets, granules and syrups containing from 200 to 2000 mg
of active principle, at a daily dosage of between 400 and 2000
mg.
Inventors: |
Ferrieri; Antonella (Tole,
IT), Rotini; Leone G. (Bologna, IT) |
Assignee: |
Alfa Wassermann S.p.A. (Alanno,
IT)
|
Family
ID: |
11338806 |
Appl.
No.: |
08/083,453 |
Filed: |
June 28, 1993 |
Foreign Application Priority Data
|
|
|
|
|
Mar 23, 1993 [IT] |
|
|
BO93A 000099 |
|
Current U.S.
Class: |
514/279 |
Current CPC
Class: |
A61K
31/44 (20130101) |
Current International
Class: |
A61K
31/44 (20060101); A61K 031/44 () |
Field of
Search: |
;514/279 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Goldberg; Jerome D.
Attorney, Agent or Firm: Bucknam and Archer
Claims
What is claimed is:
1. The method of treatment of a patient affected by gastric
dyspepsias caused by Helicobacter pylori, which consists of orally
administering to said patient a composition in unit dosage form
containing rifaximin in the amount of 200-2000 mg per dose.
2. The method according to claim 1 wherein said composition is in
the form of a tablet, a capsule, a sugar coated tablet, granules or
a syrup.
3. The method according to claim 1 wherein the total daily dose of
rifaximin is 400-2000 mgs.
Description
BACKGROUND OF THE INVENTION
The present invention relates to the treatment of gastric dyspepsia
by oral administration of rifaximin.
Two Australian microbiologists, Warren J. R. and Marshall B.,
reported in Lancet, 1983, 1, 1273-1275, that they had identified in
gastric biopsies from patients affected with gastric dyspepsia some
curved and storiform bacilli which were initially erroneously
believed to belong to the Campylobacter species. Later, Goodwin C.
S. et al, Int. J. Syst. Bact. 39, 397-405, 1989, made a more
precise classification of the micro-organism, which had no elements
in common with the Campylobacter genus, and used the name of
Helicobacter pylori, derived from the helical form of the bacterium
and from its preferred location in the pylorus. Marshall B. et al.,
Med. J. Australia, 142, 436-439, 1985 and Morris A., Nicholson G.,
Am.J. Gastroenterol., 82, 192-199, 1987, demonstrated the
pathogenic nature of this bacterium which causes gastritis in
man.
McNulty C. A. M. et al., Antimicrob. Agents Chemother., 28, (6),
837-838, 1985 and Shungu D. L. et al., Antimicrob. Agents
Chemother., 31, (6) 949-950, 1987, have demonstrated the in vitro
activity of several antibiotics against this bacterium. In
particular, they demonstrated the vigorous antibacterial in vitro
activity of antibiotics containing a beta-bactam group, penicillin,
ampicillin, cefoxttin and imipenem, quinolones: norfloxacin and
cyprofloxacin, aminoglycosides: gentamicin and erythromycin, and
also tetracycline and metronidazole and the lack of in vitro
activity of other antibacterial agents like sulfa drugs,
trimethoprim, nalidixic acid.
It has been found, however, that the proved antibacterial activity
in vitro does not automatically give the antibacterial agents a
therapeutic activity in vivo on Helicobacter pylori. Mertens J. C.
C. et al, Antimicrob. Agents Chemother., 33, 2, 256-257, 1989,
demonstrated that norfloxacin, a powerful quinolone antibiotic,
active in vitro against the bacteria with M.I.C. 90% equal to 1
.mu.g/ml, is unable to eradicate Helicobacter pylori in 15 out of
17 patients after a month of treatment.
This therapeutic failure, sharply contrasting with the proved in
vitro activity of norfloxacin against Helicobacter pylori, is
attributed both to the bacterial resistance, acquired in as many as
9 cases during the antibiotic treatment, and to the fact that the
antibiotic does not penetrate sufficiently into the deeper layers
of the gastric mucous harbouring the bacteria. The lack of
antibacterial action in vivo was further demonstrated by
histological data and by the symptoms which remained unaltered.
SUMMARY OF THE INVENTION
An object of the invention is to provide an antibiotic which is
active in vivo in patients affected by gastric dyspepsia caused by
Helicobacter pylori.
The crux of the present invention resides in the finding that
rifaximin (INN), an antibiotic belonging to the rifamycin family,
4-deoxy-4'-methyl-pyrido [1',2',:1,2] imidazo [5,4-c] rifamycin SV,
described in the Italian patent 1,154,655 and in the U.S. Pat. No.
4,341,785, demonstrates in vitro antibacterial activity against
Helicobacter pylori and is active in vivo in patients affected with
gastric dyspepsia caused by Helicobacter pylori. The antibacterial
activity of this antibiotic is similar to that of rifampin
(Venturini A. P. and Marchi E., Chemioterapia 5, (4), 257-262,
1986), but unlike rifampin has not been absorbed systematically
after oral administration (Venturini A. P., Chemotherapy, 29, 1-3,
1983 and Cellai L. et al., Chemioterapia, 3, 6, 373-377, 1984)
because of the zwitterion nature of the compound which cannot be
absorbed by the gastro-intestinal tract (Marchi E. et al., J. Med
Chem., 28, 960-963, 1985). Because of these properties, rifaximin
has no toxicity at 2000 mg/kg/p.o. in the rat, is unlikely to lead
to the formation of resistant strains and also remains active for a
long time in the stomach. Because of these properties, the present
inventors have investigated the possibility of using rifaximin as a
drug to eradicate Helicobacter pylori, a bacterium responsible for
many pathologies of the dyspeptic type, difficult to eradicate with
normal antibiotics absorbed orally and administered systematically,
which also involve serious problems of toxicity and easily provoke
resistance.
Rifaximin therefore has first been tested in vitro to gauge the
sensitivity of Helicobacter pylori towards the antibiotic and then,
after observing its action against this type of bacterium, it has
been used in vivo to treat patients with dyspeptic symptoms caused
by Helicobacter pylori. The test in vivo confirmed that rifaximin
is successful in eradicating Helicobacter pylori completely in one
half of the patients treated, an eradication found 30 days after
the end of treatment, considerable reduction in the number of
bacteria in the remaining one half of patients, a considerable
improvement of the dyspeptic syptoms, nausea, vomit, burning,
belching, epigastric weight and epigastric pain present before the
start of the therapy and total normalization or clear improvement
of the conditions of the gastric wall on histological
examination.
The object of the present invention is the use of rifaximin (INN)
and orally administered pharmaceutical formulations containing it
in the treatment of the various forms of gastric dyspepsia such as
gastritis, gastroduodenitis, antral gastritis, antral erosions,
erosive duodenitis and peptic ulcers, caused by the bacterium known
as Helicobacter pylori. All the pharmaceutical forms commonly used
for oral administration of a drug may be used within the scope of
this invention. In particular, the preferred pharmaceutical forms
acting as a vehicle for the present invention are tablets,
capsules, sugar coated tablets, granules and syrups containing from
200 to 2000 mg of rifaximin. All these pharmaceutical forms may be
prepared according to the methods known by pharmaceutical
techniques, with excipients selected among binding agents,
dispersing agents, thickeners, lubricants, colouring agents,
aromatizers, coatings and bioadhesives suitable for the prescribed
pharmaceutical form.
For the tablets, binding agents such as polyvinylpyrrolidone,
carboxymethylcellulose, microcrystalline cellulose and gelatin,
dispersing agents such as amides, sodium starch glycolate,
alginates, reticulated polyvinylpyrrolidone and reticulated sodium
carboxymethylcellulose; lubricating agents such as talc, magnesium
stearate, stearic acid, silica gel, sodium benzoate and the stearic
palmitic ester of glycerol; colouring agents such as iron oxides,
titanium dioxide, erythrosin, indigotin; coating agents such as
hydroxypropylmethylcellulose, hydroxypropylcellulose and esters of
polyacrylic acid; plasticizing agents like polyethylene glycols,
acetylated monoglycerides, triacetin and diethylphthalate;
bioadhesive agents such as polyacrylic acids, pectins,
carboxymethylcellulose, polyvinylalcohols, tragacanth and
hydroxypropylmethylcellose may be used advantageously.
In addition to the binding agents, thickeners, lubricants and
bioadhesives described for tablets, granules may also contain
sweeteners like sodium saccharin, saccharose, aspartam, xylitol,
sorbitol and aroma-adding substances such as aromas of sour cherry,
cherry, pineapple, and lemon. Besides the excipients described in
the tablets, capsules made of both hard and soft gelatin may also
contain surfactants like those known under the name of Tween.RTM.,
sodium laurylsarcosinate, saccharose monopalmitate and lipophilic
substances such as vegetable oils and oil of vaseline and
hydrophilic substances for instance polyethylene glycols in which
the gelatin is insoluble.
Lastly, the syrups may contain the same agents described for the
granules, with the addition of possible preserving agents, for
instance, paraoxybenzoates and surfactants such as those described
for the capsules. The therapeutic dose varies according to the body
weight and the acuteness of the pathology; a daily dose between 400
and 2000 mg, to be administered in a single dose or divided into 2
or 3 doses, is a suitable therapeutic dose.
The antibacterial activity of rifaximin on Helicobacter pylori has
been determined in vitro on 8 strains isolated from gastric
biopsies using concentrations of the drug between 0.03 .mu.g/ml and
16 .mu.g/ml. The minimum inhibiting concentration (M.I.C.) of
rifaximin was found to be between 0.5.mu.g/ml and 2 .mu.g/ml.
The therapeutic efficacy of rifaximin in the treatment of some
forms of gastric dyspepsia caused by Helicobacter pylori was
demonstrated by means of a clinical examination performed on 10
patients showing clear dyspeptic symptoms, nausea, vomit, burning,
belching, epigastric weight and epigastric pain and endoscopic
diagnoses of gastritis, antral erosion and erosive duodenitis, all
caused by Helicobacter pylori as shown by the serum examinations to
determine the levels of specific class G immunoglobulins against
Helicobacter pylori using the ELISA technique as described by Vaira
D. and Holton J., Gastroenterology, 97, 1069-1070, 1989.
In the form of granules marketed under the brand name NORMIX.RTM.,
rifaximin was administered for 14 consecutive days at the dose of
1800 mg per day and after 30 days from the end of treatment various
tests were performed which demonstrated the efficiency of the
treatment from the various aspects.
The clinical examination showed the almost complete disappearance
of nausea, vomit, burning, belching, epigastric weight and
epigastric pain, while the endoscopic examination showed the
disappearance of gastritis in 7 cases and improvement in 3
cases.
The microbiological examination showed complete eradication of
Helicobacter pylori in one half of the patients and a sharp
reduction of the strains present in the remaining one half, while
the histological examination revealed the normalization of the
gastric wall in patients in whom the bacterium had been eradicated
and a clear improvement of the phlogistic infiltrate with reduction
of polymorphonucleates in the remaining patients. Lastly the serum
examination showed a 20% reduction in the amount of specific
imrnunoglobulins in those patients in whom the bacterium had been
completely eradicated.
The examples described hereinbelow must be taken as a further
illustration of the invention but must not be considered as a
limitation of the invention itself.
EXAMPLE 1
Sensitivity of Helicobacter pylori to Rifaximin
8 strains of Helicobacter pylori, isolated from gastric biopsies,
were cultivated on a medium of Mueller-Hinton broth (DIFCO
0757-01-4, 9.8 mg/ml of Ca++ ions and 1.1 mg/ml of Mg++ ions)
supplemented with 2 g/l of sodium chloride and with 1.35% (W/V) of
Bitek agar (DIFCO 0138-01-4). 48 hours after seeding, 3.25% (V/V)
of defibrinated horse blood (SCLAVO 87088) or the same quantity of
horse serum (FLOW 29-211-54) was added to the medium prepared in
plates which were kept at 36.degree. C. for 7 days in a 2.5 1 jar
in microanaerobic conditions achieved using CampyPak (BBL 71034),
activated with controlled de-ionized water, without catalyzer.
10 milligrams of rifaximin were dissolved in sterile conditions in
0.6 ml of 99% methyl alcohol. The solution was diluted with 10
volumes of sterile de-ionized water and aliquots of 0.5 ml were
added to 7 ml of medium. Cells of Helicobacter pylori collected
from the medium and dissolved in Columbia broth (DIFCO 0944-05-4)
at a multiplicity of 5.times.10.sup.4 CFU/ml were deposited in a
volume equal to 10.mu.ul on the inoculation areas at the rate of
about 50 CFU/mm.sup.2 through a calibrated plastic loop. Tests were
made of concentrations of rifaximin between 0.03 .mu.g/ml and 16
.mu.g/ml and the evaluation of the minimum inhibiting dose (MIC)
gave the following results:
0.5 .mu.g/ml for 1 strain
1 .mu.g/ml for 4 strains
2 .mu.g/ml for 3 strains
EXAMPLE 2
Clinical Examination of Patients Affected with Dyspeptic Symptoms
Caused by Gastritis Colonized by Helicobacter pylori
At the Institute of Clinical Medicine and Gastroenterology of the
Sant'Orsola Hospital of Bologna, 10 patients were selected aged
between 45 and 50 years affected with dyspeptic symptoms with
endoscopic report of gastritis colonized by Helicobacter
pylori.
Seven of these patients presented diagnosis of gastritis, one of
antral erosion and two of erosive duodenitis and all were positive
to the Cp-test which indicates the presence of Helicobacter pylori
with a specificity of 100%.
All patients were treated orally with 1800 mg/day of NORMIX.RTM.,
which is the trademark for the composition containing rifaximin.
The drug was administered as granules divided into 3 daily doses
for 14 consecutive days. Thirty days after the end of the
treatment, the 10 patients were subjected to the same tests which
had been done before the start of the treatment to monitor the
success of the treatment with rifaximin.
Clinical Examination
The symptoms assessed were nausea, vomit, epigastric burning,
belching, epigastric weight and epigastric pain. The intensity of
the symptoms was expressed according to the following scale:
no sympton=0
slight=1
fair symptom=2
serious symptom=3
The statistical table below was drawn up using the exact
probability test of Fisher and the test of Wilcoxon and the
results, considered significant when the value of P was <0.05,
show a significant and almost complete disappearance of all the
symptoms considered.
TABLE 1 ______________________________________ PRE- POST-
STATISTICAL TREAT- TREAT- SIGNIFICANCE SYMPTOM MENT MENT (*)
______________________________________ NAUSEA 2.89 .+-. 0.21 0.00
.+-. 0.00 * VOMIT 1.75 .+-. 0.25 0.00 .+-. 0.00 * EPIGASTRIC 2.10
.+-. 0.11 0.18 .+-. 0.10 * BURNING BELCHING 1.80 .+-. 0.25 0.28
.+-. 0.12 * EPIGASTRIC 1.88 .+-. 0.30 0.25 .+-. 0.16 * WEIGHT
EPIGASTRIC 1.78 .+-. 0.22 0.30 .+-. 0.15 * PAIN
______________________________________
Endoscopic Examination
The endoscopic examination confirmed the clear clinical
improvement, highlighting the disappearance of the gastritis in 7
cases and a considerable reduction of erosive lesions in the
remaining 3 cases.
Histological Examination
The histological examination gave an evaluation of the presence and
amount of the bacteria and an assessment of the type of gastritis
with reference to the density and the localization of the
inflannnatory infiltrate; any presence of glandular atrophy,
intestinal metaplasia and dysplasia was also highlighted.
Before treatment with rifaximin, the histological examination of
the gastric mucous had shown a considerable infiltration of
polymorphonucleates in all the patients. Moreover, the bacteria was
present in considerable quantities in all the plates examined and
in 4 cases glandular atrophy and metaplasia were observed.
Thirty days following the end of treatment with NORMIX.RTM.,
complete normalization of the gastric histology was observed in the
5 patients in whom Helicobacter pylori had been completely
eradicated, while in the remaining 5, in whom a small quantity of
Helicobacter pylori still remained, there was a considerable
improvement of the phlogistic infiltrate with a decrease in the
number of polymorphonucleates present in the infiltrate.
Microbiological Examination
The microbiological examinations were done on samples of antral
biopsies which were used both for the rapid diagnosis of
colonization through the CP-test according to Vaira D. et al., J.
Clin. Pathol., 41, 812-813, (1988), and for the cultural isolation
of Helicobacter pylori in chocolate agar with addition of 2%
erythromycin according to Vaira O. et al., Am. J. Gastroenterol.,
85, 701-704, (1990).
These tests have confirmed the efficiency of rifaximin therapy,
showing complete eradication of Helicobacter pylori in 5 patients
and the presence of just a few colonies in the remaining 5
patients.
In addition, the test of resistance to rifaximin performed on
diagnosis on 20 strains of Helicobacter pylori did not show any
resistant strain.
Serum Examination
The serum examination was performed using the ELISA technique
according to Vaira D. et al., Gastroenterology, 97, 1069-1070,
1989. The serum examination showed a decrease in the rate of
specific class G immunoglobulins against Helicobacter pylori equal
to about 20% in the 5 patients in whom Helicobacter pylori was
eradicated.
* * * * *